Red Flags for Chronic Inflammatory Demyelinating Polyradiculoneuropathy Associated with Sarcoidosis or Connective Tissue Diseases

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare autoimmune disorder of the peripheral nervous system. Diagnosis relies on clinical and electrophysiological criteria. Various disorders requiring specific treatment regimens may be associated with CIDP, including sarcoidosis (SAR-CIDP) and connective tissue disease (CTD-CIDP). Therefore, it is important to distinguish between CIDP, SAR-CIDP and CTD-CIDP. In this retrospective monocentric study, we analyzed 16 patients with SAR-CIDP and 11 with CTD-CIDP and compared them with a group of 17 patients with idiopathic CIDP. SAR-CIDP patients had a frequently acute or subacute CIDP onset. CTD-CIDPs were mostly Sjögren’s syndrome and lupus, and patients had a chronic onset. An older age at onset (64.5 vs. 54 years, p = 0.04), more atypical presentation (19/25 (76%) vs. 6/17 (35%), p = 0.008), acute/subacute onset of symptoms (15/25 (60%) vs. 1/17 (6%), p = 0.0004) and more frequent weight loss (7/16 (44%) vs. 0/17 (0%), p = 0.017) were identified SAR-CIDP and CTD-CIDP groups. Response to intravenous immunoglobulin therapy was lower in the combined SAR-CIDP and CTD-CIDP group (44% versus 82%, p = 0.005). As sarcoidosis and CTDs might be associated with CIDP and require specific management, the “red flags” mentioned above should be kept in mind by clinicians managing patients with CIDP.


Introduction
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disorder affecting the peripheral nerves and is typically characterized by symmetrical proximal motor weakness and sensory dysfunction affecting proprioception, associated with areflexia. The diagnosis is based on clinical presentation and electrophysiological data. Nerve conduction studies (NCSs) are crucial for the diagnosis, according to the European Federation of Neurological Societies-Peripheral Nerve Society (EFNS-PNS) criteria [1]. Based on these criteria, so-called supportive diagnostic tools may be necessary for the diagnosis of CIDP: raised cerebrospinal fluid (CSF) protein level without pleiocytosis, inflammatory pattern of nerve roots and/or plexus on magnetic resonance imaging (MRI) and response to immunomodulatory treatment. Despite these supportive diagnostic 2 of 11 tools, the diagnosis of CIDP might remain challenging, and other diagnoses must be ruled out [1].
Sarcoidosis is a systemic inflammatory disorder in which peripheral nervous system (PNS) involvement is rare, representing approximately 14% of all neurological involvements [2]. Within the entities of PNS involvement in sarcoidosis, CIDP is a rare feature that may mimic idiopathic CIDP in the absence of previously known sarcoidosis [2].
Connective tissue diseases (CTDs) are autoimmune disorders that affect various organs. The most frequent CTDs consist of rheumatoid arthritis (RA), Sjögren's syndrome (SS), systemic lupus erythematous (SLE) and systemic sclerosis. PNS involvement in SS and SLE has been reported in 7% and 10% of cases, respectively [3,4], and the most common clinical patterns are sensory neuronopathy and mononeuritis multiplex. However, CIDP has rarely been described.
In patients presenting CIDP, it might be thus challenging to distinguish between idiopathic CIDP and that associated with systemic disorders such as sarcoidosis or CTDs. This is of relevance due to the impact on therapeutic decisions for the patients.
In our study, we analyzed a series of patients with CIDP associated with sarcoidosis (SAR-CIDP) and CIDP associated with CTD (CTD-CIDP) and compared them to a group of patients with idiopathic CIDP in order to identify the features pointing to diagnose an associated sarcoidosis or a CTD in the setting of CIDP.

Protocol Approval and Patient Consent
This study was accepted and achieved under the ethical guidelines issued by our institutions for clinical studies. This retrospective study was in compliance with the tenets of the Helsinki Declaration. All patients gave verbal informed consent. In our study, only retrospective medical data obtained during the care were analyzed in conformity with the French Jardé law and the Greater Paris University Hospitals' (AP-HP) requirements.

Patients
We performed a retrospective monocentric study in a French national reference center for rare polyneuropathies. Data collection ranged from 1989 to 2021. Patients were identified using a local database for inflammatory neuropathy and sarcoidosis or CTD. We included patients with definite, probable, possible or undefined CIDP depending on NCS studies, and the aforementioned support criteria according to EFNS-PNS criteria [1].
Inclusion criteria: all consecutive patients followed in our reference center for both CIDP+SARCOIDOSIS (SAR-CIDP group, n = 17) and CIDP+CONNECTIVE TISSUE DIS-EASE (CTD-CIDP, n = 11) were included via Assistance Publique-Hôpitaux de Paris APHP (APHP) open source software i2B2 using MeSH terms. There were no exclusion criteria. Neurosarcoidosis (NS) was classified as definite (granuloma found within the nervous tissue), probable (granuloma found elsewhere and neurological disorders) or possible (no granuloma found but compatible neurological disorders) according to Zajicek criteria [2].
The connective tissue diseases were defined according to the American College of Rheumatology (ACR) criteria for systemic lupus erythematosus (SLE), Sjögren's syndrome (SS) or mixed connective tissue disease [5,6].
The patients were divided into two groups according to the final diagnosis: CIDPassociated with sarcoidosis (SAR-CIDP) and CIDP-associated with CTD (CTD-CIDP). The control group (idiopathic CIDP) included consecutive patients recruited from our outpatient clinic, all fulfilling definite EFNS-PNS CIDP diagnosis [1].

Electrophysiological Studies
Electrodiagnostic studies were performed including upper-and lower-limb nerve conduction studies (NCSs) and electromyography (EMG) using a concentric needle electrode in at least 2 muscles. These analyses were performed by a unique operator (GB). Studies were achieved using regular equipment and accepted methods, and skin temperature was kept in the 32-34 • C range.

Data Collection
The following data were collected retrospectively according to the medical file of the patients: demographics (age at onset, sex), clinical presentation and neurological/systemic examination at baseline and outcome (topography, type of onset: acute/subacute or chronic as defined by [1]), cranial nerve involvement and biological data (including autoimmunity, C3/C4 levels, renal or hepatic involvement for CTD or sarcoidosis, Angiotensin I converting enzyme (ACE) serum levels and the existence of a monoclonal gammopathy). Supportive diagnostic tools included CSF findings, nerve root MRI findings and nerve and muscle biopsy findings and were analyzed. Nerve and muscle biopsies were performed according to recommendations at the time of the examination, mostly due to poor response to a first line regiment of intravenous immunoglobulin (IVIG) or suspicion of nerve vasculitis.

Statistics
Statistical analysis was performed using the R language (version 3.2.3, 2015-12-10). According to the type and distribution of the variables we used the non-parametric Wilcoxon test, Student T test, Chi2 test or Fisher exact test. When necessary, multiple testing correction was performed using the Benjamini-Hochberg method. Graphics were produced using the ggplot2 R package. A p value under 0.05 was considered significant. (Figure 1 and Table 1) A total of 44 patients (23 women, median age at symptom onset 60 yo, interquartile range (IQR) of 50-68 yo), were included in the study: 17 with CIDP, 16 with SAR-CIDP and 11 with CTD-CIDP ( Figure 1).

SAR-CIDP Group
The median age at neurological onset was 66 yo [IQR 56-73], with 44% of patients being women. All SAR-CIDP patients but one had histologically proven granuloma. There were nine definite peripheral neurosarcoidosis (NS) (9/13 positive nerve biopsies), six probable NS and one possible NS according to Zajicek criteria. The localizations of the granuloma defining the sarcoidosis are summarized in Table 2. Ten had NS diagnosis within one year and three had one between one and three years after neurological onset. In two patients (12.5%), sarcoidosis was already diagnosed at its neurological onset.
Among SAR-CIDP patients, 14 NCSs were available. The patients were classified as having definite (n = 5), probable (n = 2), possible (n = 3) and undefined (n = 4) CIDP according to EFNS-PNS criteria. After correction for supportive criteria, they were classified as definite PIDC in eight cases, possible in one, probable in one and undefined in four ( Figure 1).

CTD-CIDP Group
The median age at neurological onset was 62 yo [IQR 53-67], with 82% being women. Diagnoses were SS (n = 7), SLE (n = 1), SLE associated with SS (n = 2) and mixed connective tissue diseases (n = 1). Three patients had CTD diagnosed within one year and four patients between 1 and 15 years after neurological onset. In four patients (36%), the CTD was already diagnosed at neurological onset.
NCSs classified patients as having definite (n = 4), possible (n = 3) and undefined (n = 4) CIDP according to EFNS-PNS criteria. After correction for supportive criteria, they were classified as having definite CIDP in six cases, probable in one and undefined in four ( Figure 1).
Concerning the therapeutic response, IVIGs were effective in 7/11 (64%) patients, while steroids were effective in 5/5 patients when used. Five patients had received an immunomodulatory drug during their medical history, but this effect on the CIDP could not be evaluated.

SAR-CIDP Group
The median age at neurological onset was 66 yo [IQR 56-73], with 44% of patients being women. All SAR-CIDP patients but one had histologically proven granuloma. There were nine definite peripheral neurosarcoidosis (NS) (9/13 positive nerve biopsies), six probable NS and one possible NS according to Zajicek criteria. The localizations of the granuloma defining the sarcoidosis are summarized in Table 2. Ten had NS diagnosis within one year and three had one between one and three years after neurological onset. In two patients (12.5%), sarcoidosis was already diagnosed at its neurological onset.
Among SAR-CIDP patients, 14 NCSs were available. The patients were classified as having definite (n = 5), probable (n = 2), possible (n = 3) and undefined (n = 4) CIDP according to EFNS-PNS criteria. After correction for supportive criteria, they were classified as definite PIDC in eight cases, possible in one, probable in one and undefined in four (Figure 1).

Discussion
The diagnosis of CIDP can be challenging because of atypical neurological presentation [1] and the need to exclude differential or associate diagnoses. The treatment of idiopathic CIDP relies on immunomodulation with IVIG, steroids or plasmapheresis. Atypical features ("red flags") such as unresponsiveness to treatment, general symptoms, cytopenia and rapid evolution should prompt clinicians to consider an underlying diagnosis of CIDP [1,7]. Indeed, CIDP may be associated with other diseases, such as sarcoidosis or CTD, that modify disease management.
The aim of our study was to describe distinctive features that may help identify associated sarcoidosis or CTD in CIDP patients, which has never been done. We identified several distinctive features (red flags): more frequent weight loss, unresponsiveness to IVIG therapy and acute onset of symptoms in SAR-CIDP. CTD-CIDP patients had more frequent weight loss and cytopenia. Interestingly, CSF protein levels and other biological findings, including ACE levels and calcemia, did not differ between groups which is consistent with previous studies. Extra-neurological involvements were more frequent, as expected. Thus, we recommend a comprehensive clinical examination and a larger work-up

Discussion
The diagnosis of CIDP can be challenging because of atypical neurological presentation [1] and the need to exclude differential or associate diagnoses. The treatment of idiopathic CIDP relies on immunomodulation with IVIG, steroids or plasmapheresis. Atypical features ("red flags") such as unresponsiveness to treatment, general symptoms, cytopenia and rapid evolution should prompt clinicians to consider an underlying diagnosis of CIDP [1,7]. Indeed, CIDP may be associated with other diseases, such as sarcoidosis or CTD, that modify disease management.
The aim of our study was to describe distinctive features that may help identify associated sarcoidosis or CTD in CIDP patients, which has never been done. We identified several distinctive features (red flags): more frequent weight loss, unresponsiveness to IVIG therapy and acute onset of symptoms in SAR-CIDP. CTD-CIDP patients had more frequent weight loss and cytopenia. Interestingly, CSF protein levels and other biological findings, including ACE levels and calcemia, did not differ between groups which is consistent with previous studies. Extra-neurological involvements were more frequent, as expected. Thus, we recommend a comprehensive clinical examination and a larger work-up including thoracic X-ray, serum protein electrophoresis, auto-antibody testing and accessory salivary gland biopsy in case of the aforementioned red flags. In our study, MSGB, considered as minimally invasive, revealed granuloma in 29% (2/7) of SAR-CIDP patients, which is close to findings regarding the diagnostic accuracy of MSGB in sarcoidosis [42]. In the CTD group, the Chisolm score was consistent with Sjögren's syndrome in 7/10 patients. Globally, MSGB contributed to diagnosis in more than 50% of cases.
Interestingly, SAR-CIDP and CTD-CIDP patients fulfilled definite EFNS/PNS CIDP diagnosis criteria in more than 50% of cases (respectively, 54% and 57%) and motor conduction blocks were equally found in both the SAR-CIDP and CIDP groups (47% vs. 83%, respectively, (p = 0.12). These results are consistent with the literature [8,11] with the hypothesis of a mechanical action of the granuloma in a nerve conduction bloc [11]. However, we found specific demyelinating lesions within 9/12 (69%) of the nerve biopsies of the SAR-CIDP group, and one patient had a characteristic "onion bulb". These features were distinct from the granulomas' locations, which suggests a primary demyelinating process in SAR-CIDP. Surprisingly, there were no differences in nerve biopsies between SAR-CIDP and CIDP concerning the inflammatory component either in its quantitative or qualitative features. Finally, associated muscle biopsy increased the sensitivity of nerve biopsy since granuloma findings increased from 69% to 87% of cases (Table 2).
Concerning the response to treatment, our results showed a good response to classic treatment regimen with IVIG use in CTD-CIDP patients on the one hand, whereas on the other hand, use of corticosteroids was needed in SAR-CIDP patients due to resistance to IVIG. One explanation could be the sarcoid granuloma's involvement in nerve demyelination, either via mechanical component or via a paracrine effect.
Our study has several limitations. Due to the retrospective nature of the data collection, we cannot rule out bias in the selection or the interpretation of some clinical parameters. Additionally, we were unable to collect the exact cumulative dose of corticosteroids in the SAR and CTD groups to evaluate their precise impact. Further, we could not analyze the precise effect of other immunomodulatory drugs in these patients.

Conclusions
In conclusion, although SAR-CIDP and CTD-CIDP share some common features with CIDP, our study suggests that acute onset, cytopenia, weight loss and non-response to IVIG treatment are good criteria that may indicate the existence of an underlying inflammatory disease in a patient with CIDP. As sarcoidosis and CTDs require specific management, these red flags should be kept in mind by clinicians managing patients with CIDP.  Informed Consent Statement: This study was accepted and achieved under the ethical guidelines issued by our institutions for clinical studies. This retrospective study was in compliance with the tenets of the Helsinki Declaration. All patients gave verbal informed consent. Data Availability Statement: Data are available upon request by the corresponding author.